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Perturbations of Enzymic Uracil Excision due to Guanine Modifications in DNA¹

Department of Pathology and Fels Research Institute, Temple University School of Medicine, Philadelphia, Pennsylvania 19140

Phage PBS2 DNA, which contains uracil in place of thymine, was used as substrate for purified Bacillus subtilis uracil:DNA glycosylase. Incubation of this DNA with the ultimate carcinogen N-acetoxy-N-2-acetylaminofluorene resulted in the production of N-(deoxyguanosin-8-yl)acetylaminofluorene. A decreased V_max resulted from the reaction of the glycosylase with this arylamidated substrate. Addition of a 2-fold excess of control PBS2 DNA following initiation of the reaction with the modified substrate showed delayed dissociation of the enzyme from the arylamidated DNA. This shows that the presence of a carcinogen-modified DNA base can reduce the capacity for uracil excision. Therefore, interference with enzymic release of uracil from DNA may be an indirect mechanism of mutagenesis by carcinogen:DNA adducts.

¹ This work was supported by USPHS Grants ES-02935 from the National Institute of Environmental Health Sciences and CA-12923 from the National Cancer Institute.

² Recipient of USPHS Research Career Development Award 1KO4-CA-00796 from the National Cancer Institute. To whom requests for reprints should be addressed.

Received 5/ 5/83. Accepted 11/ 8/83.